Topixantrone (BBR 3576) is a hetero-analog of the anthrapyrazole class of compounds. The mechanism of action of BBR 3576 is similar to that of mitoxantrone in terms of DNA intercalation, DNA affinity, topoisomerase II interaction and formation of single-strand breaks. BBR 3576 showed curative antitumor activity at the maximum tolerated dose (MTD) with a number of long-term survivors and showed greater activity than mitoxantrone and doxorubicin in preclinical studies. BBR 3576 retained a high level of activity across a wide range of doses. In human xenograft studies, equivalent antitumor activity was observed when compared with doxorubicin and mitoxantrone. The compound showed reduced cardiotoxicity when repeatedly administered in rodent models. Topixantrone has a manageable toxicity profile on a 4-week schedule.

Nitracrine (Ledakrin, C-283) is an acridine derivative with potential cytostatic and antitumor activities. Nitracrine induces the unwinding of supercoiled DNA and binds to the DNA through intercalation, forming drug-DNA adducts and DNA interstrand crosslinks. This inhibits RNA synthesis, protein production, cell growth, DNA replication and cell proliferation; altogether, this may promote apoptosis. Since cancer cells have increased metabolism and proliferate at an increased rate, nitracrine may induce tumor cell apoptosis. The drug was used in clinics in Poland for the treatment of ovarian, colon, lung and mammary carcinomas. Some undesirable effects observed in clinics: e.g. nausea, vomiting and toxicity and mutagenicity of the drug in S. typhimurium strongly limited the therapeutic use of nitracrine and promoted a search for more suitable analogues.

13-deoxyadriamycin hydrochloride (13-Deoxydoxorubicin hydrochloride, GPX-100) is an anthracycline similar to doxorubicin. GPX-100 is unique among anthracyclines because it is not converted to doxorubicinol during metabolism in the body. This metabolite has been shown to be a major cause of damage to the heart (cardiotoxicity) in laboratory studies. GPX-100 belongs to the class of reactive oxygen species stimulants; RNA synthesis inhibitors and Type II DNA topoisomerase inhibitors. It was in phase II clinical trial for the treatment of cancer.

PM-060184 is a new type of marine polyketide isolated from the Madagascan sponge. PM060184 belongs to a new family of tubulin-binding agents. PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. PM-060184 demonstrated antimitotic properties in human tumor cells lines at subnanomolar concentrations and display a distinct inhibition mechanism on microtubules. An antivascular mechanism is contributing to the antitumor activities of plocabulin. PM-060184 I in phase II clinical trial for the treatment of breast and colorectal cancer.

Echinomycin is a cyclic peptide of the family of quinoxaline antibiotics that was originally isolated from Streptomyces echinatus. It is thought to act as a bifunctional DNA intercalator. Echinomycin has a binding site size of four base pairs. The strong binding sites for echinomycin contain the central two-base-pair sequence 5'-CG-3'. Echinomycin interferes with HIF-1 DNA binding in a sequence-specific fashion. It was brought into clinical trials by the NCI 20 years ago based on its antitumor activity. It has been extensively tested in phase I-II clinical trials. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. However, minimal or no antitumor activity was found in phase II clinical trials.

Zorbamycin (U-30,604E), an antibiotic that induced rapid degradation of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in Bacillus subtilis cells. It was shown that this drug somehow induced a change in the structure or function of the cellular DNA fraction which resulted in rapid breakdown of this fraction. Zorbamycin also possesses antitumor activity.

Kirax Corporation (formerly Tigris Pharmaceuticals) was developing AFP-464, a lysyl prodrug of aminoflavone for the treatment of solid tumours. AFP-464 is an antitumor agent which was in phase II clinical trials, acts against estrogen-positive breast cancer (ER+). AFP-464, has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway. Preclinical studies into AFP-464's mechanism of action have shown that AFP-464 is converted to metabolites, which bind covalently to DNA, resulting in p53 activation and apoptosis. AFP-464 has shown a unique pattern of growth inhibitory activity in the NCI's 60 tumor cell line screen, with breast, ovarian, lung and renal tumor cell lines exhibiting particular sensitivity to the compound. In vivo anti-tumor activity of AFP-464 has been demonstrated in several xenograft studies in mice bearing renal and breast cancer. Preclinical studies have shown that tumors (breast, ovarian, pancreatic and renal) with AhR localized in the cytoplasm are very sensitive to AFP-464 while those with AhR localized in the nucleus are more resistant. AFP-464 was being studied by Tigris Pharmaceuticals in a randomized Phase 2 clinical trial with ER-positive breast cancer patients. However, AFP-464 development was discontinued.

GPX-150 is an anthracycline compound that is being tested for treatment in patients with soft-tissue sarcomas. This doxorubicin (DOX) analog does not show the cumulative dose-dependent cardiotoxicity of DOX. It works by reducing the formation of reactive oxygen species and the cardiotoxic metabolite, doxorubiciniol, the two pathways that are linked to the irreversible cardiotoxicity seen with DOX. Phase 1 clinical trials showed no irreversible, cumulative dose-dependent cardiotoxicity. A phase 2 study investigating the safety and efficacy of GPX-150 in patients with soft tissue sarcoma has been completed. No patients developed any evidence of irreversible, cumulative dose-dependent chronic cardiotoxicity. Toxicities reported include grade 3 anemia, neutropenia, and grade 4 leukopenia.

Pyrazoloacridine is a pyrazolo[3,4,5-kl]acridine derivative patented by Warner-Lambert Co. as an anticancer agent. Pyrazoloacridine acts as topoisomerase I and II inhibitor that decrease the formation of topoisomerase-DNA adducts. In vitro experiments, Pyrazoloacridine shows efficacy against multidrug-resistant neuroblastoma doxorubicin-resistant human colon carcinoma and breast cancer cell lines. In clinical trials, Pyrazoloacridine demonstrates moderate efficacy in metastatic breast cancer and a high level of adverse events. The dose-limiting toxicity was grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting, nausea, neurotoxicity, fatigue, and anemia.

Acridine carboxamide (XR5000) is a tricyclic acridine-based (or carboxamide-based) drug with dual topoisomerase inhibitor and potential antineoplastic activities. Acridine carboxamide inhibits both topoisomerases I and II and intercalates into DNA, resulting in DNA damage, the disruption of DNA repair and replication, the inhibition of RNA and protein synthesis, and cell death. Acridine carboxamide has been used in trials studying the treatment of lung cancer and brain and central nervous system tumors. In clinical trials acridine carboxamide did not show efficacy when tested against various types of cancers.